Dowling–Degos disease with mutations in POFUT1 is clinicopathologically distinct from reticulate acropigmentation of Kitamura-猫眼课题宝

DOI：

10.1111/bjd.13702

发表时间：

2015-08

期刊：

British Journal of Dermatology

影响因子：

10.3

通讯作者：

中科院分区：

医学1区

文献类型：

作者：

M. Kono;M. Suganuma;H. Takama;I. Zarzoso;M. Saritha;D. Bodet;S. Aboobacker;K. Kaliaperumal

亲爱的编辑，Dowling-Degos病(DDD)是一种罕见的常染色体显性遗传性色素性疾病，特征是点状或网状、轻微凹陷、边界清晰的棕色斑点，尤其影响屈曲和其他主要皮褶(图1A)。北村脱发和网状肢端色素沉着(RAK；MIM#615537)具有相似的皮肤表现，但主要影响手部和脚的背部，对于它们是同一疾病的不同临床实体或变体，长期以来一直存在争议。一些报道表明，RAK和DDD是相同的疾病，但谱系不同。DDD的致病基因于2006年被明确为Krt5，最近又发现了POFUT1(编码蛋白O-岩藻糖基转移酶1)和POGLUT1。至于RAK，2013年被证明是由于ADAM10的突变。在本研究中，我们对3个DDD家系和1个RAK家系进行了基因诊断，以阐明经遗传证实的DDD和RAK之间的差异。我们比较了DDD患者和RAK患者的详细临床和组织学特征，这两个患者分别被证实存在POFUT1和ADAM10基因突变，包括以前报道的病例。如前所述，对每个基因进行突变搜索。患者的知情同意和血液样本是根据名古屋大学医学院伦理审查委员会批准的方案获得的。此外，还对皮损活检标本进行了组织病理学检查。本研究纳入来自3个无关家系的4例DDD患者，他们分别具有POFUT1中已知的杂合突变c.397C&gt；T(p.Arg133X)(家系D1)或新突变c.460C&gt；T(p.Gln154X)(家系D2)或c.891G&gt；A(p.Trp297X)(家系D3)(图S1和S2a-c；见辅助信息)。本研究还包括来自一个家系的两名RAK患者，他们在ADAM10中具有新的杂合突变C.1000G&gt；A(p.Gly334Arg)(家系R1)。S2d，e)。此外，我们参考了我们小组以前报告的9例RAK和Li等人报告的2例DDD。(表S1；见支持信息)。POFUT1突变的DDD患者的组织病理学特征是表皮棘皮病，紧密的指状网脊，顶端明显的色素沉着，色素尿失禁和小角化的囊(图1E)。组织病理学检查显示，ADAM10突变的RAK患者的表皮表现为网脊顶端的色素沉着，网脊轻微延长变薄，表皮变薄，轻度角化过度，无角化异常或色素尿失禁(图1F)。POFUT1和POGLUT1都参与了Notch途径。角质形成细胞特异性的Notch1基因缺失会导致显著的表皮增生。这些研究结果可能支持DDD和RAK在组织病理学上的差异。因此，DDD皮损表现为棘皮病，伴有紧密的指状网脊，尽管ADAM10基因缺陷的小鼠表现出表皮棘层变薄。在黑素细胞方面，虽然ADAM10基因缺陷的小鼠没有表现出色素沉着的变化，但ADAM10基因缺陷的无毛小鼠出现了色素斑块。缺口信号也可能影响黑素细胞谱系。在小鼠中，Notch信号的遗传消融导致胚胎黑素母细胞的急剧减少和初始毛发色素的稀释。然而，目前尚不清楚这些研究结果与人类色素沉着疾病的发病机制之间的关系。DDD和RAK患者的发病年龄和皮损分布也不同(表S1)。RAK发病年龄较DDD早，DDD发病年龄18~56岁，平均28 8 13 9岁；RAK发病年龄5~12岁，平均9 2 2 2岁。在这项研究和我们之前的报告中，所有11名RAK患者中，有10名患者最初在手背有皮肤损害。相比之下，在有原始部位信息的五名DDD患者中，有四名患者的原发皮肤损害发生在手背以外的位置。粉刺样毛囊丘疹仅见于DDD患者(图1C)，而在任何RAK患者中均未见。肛周和生殖器区域的色素沉着和丘疹也仅见于DDD患者(图1D)，而RAK患者则未见。除D3-1外，其余DDD患者均有累及四肢的皮肤表现。有趣的是，所有它们的突变都是POFUT-1 N端三分之一的截断突变，取消了蛋白质氨基酸序列的C端三分之二(图1G)。相比之下，病例D3-1显示了一种临床上罕见的生殖器病变；组织病理学上，棘皮病和指状网脊相对较轻，尽管顶端的色素沉着仍然很明显。病例D3-1中的POFUT1截断突变导致

DEAR EDITOR, Dowling–Degos disease (DDD) is a rare autosomal dominant genetic pigmentary disorder characterized by dot-like or reticulate, slightly depressed, sharply demarcated brown macules particularly affecting the flexures and other major skinfolds (Fig. 1a). There has long been controversy over whether DDD and reticulate acropigmentation of Kitamura (RAK; MIM #615537), which has similar skin manifestations but affects mainly the dorsa of the hands and the feet, are distinct clinical entities or variants of the same disease. Several reports have suggested that RAK and DDD are identical disorders with different spectra. The causative gene of DDD was clarified as KRT5 in 2006, and recently also POFUT1 (encoding protein O-fucosyltransferase 1) and POGLUT1 were identified. As for RAK, it was shown to be due to mutations in ADAM10 in 2013. In this study, to clarify the differences between genetically confirmed DDD and RAK, we performed genetic diagnoses of three DDD pedigrees and one RAK pedigree. We compared the detailed clinical and histological features between patients with DDD and patients with RAK, who were confirmed to have the causative POFUT1 and ADAM10 gene mutations, respectively, including previously reported cases. The mutation search for each gene was performed as previously described. Informed consent and blood samples of patients were obtained under protocols approved by the ethics review committee of Nagoya University School of Medicine. In addition, histopathological examinations of biopsy specimens from the skin lesions were performed. Four patients with DDD from three unrelated families, who had the known heterozygous mutation c.397C>T (p.Arg133X) (family D1) or the novel mutations c.460C>T (p.Gln154X) (family D2) or c.891G>A (p.Trp297X) (family D3) in POFUT1, were included in the present study (Figs S1 and S2a–c; see Supporting Information). Two patients with RAK from one family who had the novel heterozygous mutation c.1000G>A (p.Gly334Arg) (family R1) in ADAM10 were also included in the present study (Fig. S2d,e). In addition, we referred to nine cases of RAK previously reported by our group and two cases of DDD reported by Li et al. (Table S1; see Supporting Information). The histopathological features of the patients with DDD with the POFUT1 mutations were acanthosis of the epidermis, tight digitiform rete ridges with prominent hyperpigmentation at the tips, pigmentary incontinence and small cornified cysts (Fig. 1e). In contrast, histopathological investigation revealed that the epidermis of the patient with RAK with the ADAM10 mutation showed pigmentation at the tip of the rete ridges, slight elongation and thinning of the rete ridges, thinning of the epidermis and slight hyperkeratosis without parakeratosis or pigmentary incontinence (Fig. 1f). Both POFUT1 and POGLUT1 are involved in the Notch pathway. Keratinocyte-specific deletion of the Notch1 gene results in marked epidermal hyperplasia. These investigational results may support the idea of histopathological differences between DDD and RAK. Thus, DDD skin lesions show acanthosis with tight digitiform rete ridges, although Adam10-deficient mice show thinning of the spinous layers of the epidermis. Regarding melanocytes, although Adam10-deficient mice show no alteration of pigmentation, Adam10-deficient hairless mice show pigmented macules. Notch signalling may also affect the melanocyte lineage. Genetic ablation of Notch signalling in the mouse results in a dramatic reduction of embryonic melanoblasts and a dilution of initial hair pigmentation. However, it is still unknown how these research results relate to the pathogenesis of pigmentation diseases in humans. The age at onset and the distribution of the skin lesions also differ between DDD and RAK (Table S1). RAK has an earlier age of onset than DDD: the age of onset for DDD ranges from 18 to 56 years, averaging 28 8 13 9 years, whereas the onset age for RAK ranges from 5 to 12 years, averaging 9 2 2 2 years. Among all of the 11 patients with RAK in this study and in our previous report, 10 had the initial skin lesion on the dorsa of the hands. In contrast, four of the five patients with DDD with information available on the primary sites had the primary skin lesions at locations other than the dorsa of the hands. Comedo-like follicular papules were seen only in the patients with DDD (Fig. 1c) and not in any patient with RAK. Hyperpigmentation and papules on the perianal and genital regions were also seen only in patients with DDD (Fig. 1d) and not in RAK. All of the patients with DDD except D3-1 showed skin manifestations involving the limbs. Interestingly, all of their mutations were truncation mutations around the N-terminal third of POFUT-1, abolishing the C-terminal two-thirds of the amino acid sequence of the protein (Fig. 1g). In contrast, case D3-1 showed a clinically rare genital lesion; histopathologically, the acanthosis and digitiform rete ridges were relatively mild, although the hyperpigmentation at the tips still stood out. The POFUT1 truncation mutation in case D3-1 results in

Dowling–Degos disease with mutations in POFUT1 is clinicopathologically distinct from reticulate acropigmentation of Kitamura

文献摘要

被引文献

相似文献